Prospective epidemiological studies have shown a strong association between low density lipoprotein-cholesterol (LDL-C) levels and cardiovascular disease (CVD) risk.
Hydroxy-methylglutaryl coenzyme A reductase (hereinafter: HMG CoA reductase) is an enzyme in the lever that functions in the production of cholesterol. Inhibition of HMG CoA reductase by HMG CoA reductase inhibitors, commonly referred to as “statins”, has been shown to reduce the level of LDL-C in the blood by reducing the production and accelerating uptake of cholesterol. The application of such statin therapy to decrease these LDL-C levels in the blood have resulted in a marked reduction of CVD-related morbidity and mortality. However, there are safety issues associated with HMG CoA reductase inhibitors. Particularly at high doses, they may cause increases in liver enzymes and myopathy and occasionally rhabdomyolysis, which may lead to death from acute reneal failure.
Furthermore, several studies have shown that also a low plasma concentration of high-density lipoprotein (HDL-C) is a powerful risk factor for the development of cardiovascular diseases. One new approach which reduces LDL-C and elevates HDL-C levels is to inhibit the Cholesterol Ester Transfer Protein (CETP). CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (A Apo B)-containing particles (mainly LDL and VLDL) in exchange for triglycerides, thereby decreasing the cholesterol content in HDL in favor of that in (V)LDL. Hence, CETP inhibition has been hypothesized to retain cholesteryl esters in HDL-C and decrease the cholesterol content of the atherogenic Apo B fraction.
Despite the evidence supporting the potential of CETP inhibition in reducing cardiovascular morbidity, clinical development of CETP inhibitors has not been straightforward. The first compound to progress to phase 3 clinical trials was torcetrapib which was dosed at 60 mg. Torcetrapib was shown to increase HDL-C by 72% and decrease LDL-C by 25%, but it was subsequently withdrawn from development owing to safety concerns including an unexpected increase in cardiovascular events and death when used in combination with the HMG CoA reductase inhibitor atorvastatin.
Although the mechanism of those events is not fully understood, there is increasing evidence that they might have been due to off-target effects of torcetrapib such as increased blood pressure, changes in electrolytes (increases in sodium and bicarbonate and decreases in potassium) and increases in aldosterone, consistent with mineralocorticoid activity. There is also some evidence from animal studies that torcetrapib increases expression of endothelin-1, which has been postulated to be have contributed to the apparent (non-significant) increase in cancer deaths in the ILLUMINATE trial. These observations could be related to the relatively high dose of torcetrapib needed.
Subsequently, another CETP inhibitor, dalcetrapib, entered clinical trials. Dalcetrapib was shown to be a weak inhibitor that increased HDL-C by 30-40% with minimal effects on LDL-C concentrations. Dalcetrapib development has also been terminated on the grounds of futility in a Phase 3 study where the drug was dosed at 600 mg. Lack of efficacy was probably related to modest CETP inhibition (18).
Two more CETP inhibitors, anacetrapib and evacetrapib, are currently in phase 3 clinical trials. Data from phase 2 studies suggest that both are CETP inhibitors without mineralocorticoid activity. Anacetrapib 200 mg once daily has been shown to increase HDL C by 97% and decrease LDL-C by 36% in fasted healthy subjects (21) and 150 mg once daily anacetrapib has been shown to increase HDL C by 139% and decrease LDL-C by 40% in patients (22). However, anacetrapib accumulates in fat tissue and as a consequence of this has a undesirable half life of 2-4 years in humans. Evacetrapib (500 mg once daily monotherapy in patients) has been shown to increase HDL-C by 129% and decrease LDL-C by 36% (23).
In the ongoing Phase 3 studies, a once daily dose of 100 mg anacetrapib is being clinically evaluated, whereas for evacetrapib a once daily dose of 130 mg is being evaluated. Such relatively high amounts of active ingredients may however lead to serious problems, and may present serious issues when formulating combination products thereof.
A disadvantage of the use of the known CETP-inhibitors is that due to the relatively high dosage which has to be used to obtain CETP-inhibition, more and stronger side effects may occur. This can have a negative influence on both the physical well-being of the patient as well as on patient compliance.
It has thus been difficult to use CETP-inhibitors in combination with other pharmaceutically active compounds. More particularly, in view of the existing side effects of HMG CoA reductase inhibitors and the relatively high dose of the known CETP-inhibitors, combining these inhibitors in a pharmaceutical combination has proven to be problematic, as has been observed when the combination of Torcetrapib and atorvastatin was clinically tested.
Hence, a continuing need remains to find convenient, safe and effective agents or combination of agents for use in the treatment of subjects suffering from or having an increased risk for cardiovascular diseases.